Cell signaling and transcription factors in pancreatic islet development and function

胰岛发育和功能中的细胞信号传导和转录因子

基本信息

批准号：
10370067
负责人：
David Lorberbaum
金额：
$ 9.15万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10370067
关键词：
Address Adult Advisory Committees Affect B cell differentiation B-Cell Acute Lymphoblastic Leukemia B-Cell Development Beta Cell Blood Glucose Cause of Death Cell physiology Cells Cessation of life DNA Data Defect Development Diabetes Mellitus Disease Embryo Endocrine Engineering Enzymes Epitopes Excision Follow-Up Studies Functional disorder GATA6 transcription factor Genes Genetic Transcription Human In Vitro Individual Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Knowledge Literature Maintenance Mature B-Lymphocyte Mediating Mediator of activation protein Minor Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Pancreas Pathway interactions Patients Persons Phenotype Physiological Pilot Projects Play Population Process Protocols documentation Regulatory Pathway Replacement Therapy Reporting Research Role Signal Transduction Specific qualifier value Structure of beta Cell of islet Testing Therapeutic Therapeutic Intervention To specify Transplantation Tretinoin United States WNT Signaling Pathway Work beta cell replacement blood glucose regulation cell replacement therapy cofactor cost cost estimate diabetes management differentiation protocol endocrine pancreas development genetic analysis human pluripotent stem cell improved in vivo in vivo Model innovation islet mouse model novel pancreas development pancreatic islet function prevent progenitor synergism tool transcription factor

项目摘要

PROJECT SUMMARY AND ABSTRACT Over the past several decades the number of people in the United States with diabetes has steadily increased and reports from 2020 indicate nearly 10.5% of the population have the disease, leading to more than 270,000 deaths and an estimated cost of $327 billion. While tremendous effort is directed towards managing diabetes, there is no cure. One promising treatment is islet replacement therapy, addressing a major underlying issue in both type 1 and type 2 diabetes: dysfunctional and dying β cells. This treatment, however, is not widely accessible because of a lack of donor material. To overcome this limitation, insulin producing β cells can be generated from human pluripotent stem cells (hPSCs) in vitro, but despite great strides even the best protocols are unable to efficiently produce mature β cell populations for transplant. To improve this therapeutic strategy, it is essential to clarify mechanisms of pancreas development using in vivo models that will allow us to refine β cell differentiation protocols. Nearly all of the information used to formulate these protocols is derived from developmental studies in mice, which have provided a roadmap specifying the sequential addition or removal or signaling factors to promote β cell formation. For example, retinoic acid (RA) is included in early stages of all β cell differentiation protocols to specify pancreatic progenitors simulating numerous studies conducted in mice. Despite its importance at the onset of pancreas development, little is known about RA later in mouse or human pancreagenesis. To address this knowledge gap, we performed studies that identified a novel role for RA during endocrine progenitor specification where RA represses WNT signaling to promote β cell differentiation. Since RA clearly does not act alone in this process, I also began to examine the role of GATA factors during pancreas development as well, since previous work has demonstrated RA-GATA synergy in several models, including human β cell differentiations. Furthermore, haploinsufficiency of GATA6 in humans leads to pancreas agenesis in more than 50% of cases, yet this same deletion in mice and human β cell differentiations results in minor phenotypes, suggesting that background modifiers, like RA signaling, could be playing a major role. My preliminary studies described in this proposal demonstrate significant synergy between RA and GATA TFs in mice: simultaneous inhibition leads to drastically fewer and dysfunctional endocrine cells that contributes to severe physiological defects during development and adulthood. With guidance from these preliminary data, I will clarify the regulatory mechanisms defining endocrine specification, β cell development, and islet function by testing the hypothesis that synergy between RA signaling and GATA transcription factors is essential for embryonic pancreas development and adult islet function.

项目概要和摘要过去几十年来，美国糖尿病患者人数稳步增加 2020 年的报告显示，近 10.5% 的人口患有这种疾病，导致超过 270,000 人患病死亡人数和预计成本达 3270 亿美元虽然人们为控制糖尿病付出了巨大的努力，一种有希望的治疗方法是胰岛替代疗法，它解决了一个主要的根本问题。 1 型和 2 型糖尿病：β 细胞功能失调和死亡，但这种治疗方法并不广泛。由于缺乏供体材料，可以使用产生胰岛素的 β 细胞来克服这一限制。体外由人类多能干细胞 (hPSC) 产生，但尽管取得了巨大进步，但即使是最好的方案无法有效产生用于移植的成熟 β 细胞群。使用体内模型阐明胰腺发育机制至关重要，这将使我们能够改进β 几乎所有用于制定这些方案的信息都来自于细胞分化方案。小鼠发育研究，提供了指定顺序添加或删除的路线图或促进β细胞形成的信号因子，例如，视黄酸（RA）包含在所有早期阶段。 β细胞分化方案，用于指定胰腺祖细胞，模拟在尽管 RA 在胰腺发育开始时很重要，但对小鼠或小鼠后期的 RA 知之甚少。为了解决这一知识差距，我们进行了研究，确定了人类胰腺发生的新作用。内分泌祖细胞规范期间的 RA，其中 RA 抑制 WNT 信号传导以促进 β 细胞由于RA显然在这个过程中并不单独起作用，我也开始研究GATA的作用。胰腺发育过程中的因素也是如此，因为之前的工作已经证明了 RA-GATA 的协同作用多种模型，包括人类 β 细胞分化此外，人类中 GATA6 的单倍体不足。超过 50% 的病例会导致胰腺发育不全，但小鼠和人类 β 细胞中也存在同样的缺失分化导致较小的表型，这表明背景修饰因子，如 RA 信号传导，可能是我在该提案中描述的初步研究表明了显着的协同作用。小鼠中 RA 和 GATA TF 之间的比较：同时抑制会导致 RA 和 GATA TF 显着减少且功能失调内分泌细胞在发育和成年期间导致严重的生理缺陷。根据这些初步数据的指导，我将阐明定义内分泌规范的调节机制，通过测试 RA 信号传导和 GATA 之间协同作用的假设来研究 β 细胞发育和胰岛功能转录因子对于胚胎胰腺发育和成人胰岛功能至关重要。